Cell transplantation of non-cardiac origin cells into myocardium is an attractive approach for restoring lost cardiac function, however, the electrical function of transplanted cells remains poorly understood. The transplanted cells are unlikely to communicate electrically as native cardiomyocytes do within the cardiac syncytium. In fact, the communication between cardiac and non-cardiac cells may be pro-arrhythmic, as preliminary reports have suggested. Thus, it is crucial to define the requirements for safe and effective electrical communication between transplanted non-cardiac cells and host cardiomyocytes. Cardiac excitability is determined by membrane ion channel activity and cell-to-cell coupling via cardiac gap junctions. Our preliminary studies indicate that primary cardiac cells can couple and electrically communicate with embryonic stem cell derived cardiomyocytes, but it is not clear that this communication is sufficient to be functional within a cardiac synctium. Our computer simulations have demonstrated that decreased gap junction coupling can lead to sustained ventricular arrhythmias. We are developing an in vitro experimental system in which labeled primary ventricular cardiomyocytes are co-cultured with embryonic stem cell derived cardiomyocytes and skeletal myocytes. We perform dual cell patch clamping to quantify the electrical communication between cell pairs and use these data with computer models to determine arrhythmogenic potential of regions of transplanted cells. As our preliminary data indicate that limited gap junction coupling can be arrhythmogenic, we will experimentally overexpress coupling protein and repeat assessment of coupling conductance and arrhythmogenesis. The proposed studies seek to establish the mechanisms of electrical communication between primary ventricular myocytes and putative candidates for cellular transplantation. The results will provide insight into the electrical impact of cells transplanted into ventricular myocardium, and lead to a therapeutic approach to decrease their arrhythmogenic behavior.